Tyrosine hydroxylase (TH) from rat neostriatum shows an increase in affinity for pteridine cofactors after administration of antipsychotic drugs. This correlates with an increased firing rate of nigroneostriatal dopamine (DA) neurons and an increase in biosynthesis of DA in neostriatum. We have found that discrete lesions of neuronal pathways descending from striatum to substantia nigra (SN) abolishes the ability of antipsychotics to cause activation of striatal TH. These lesions resulted in a 60-90 percent decrease of GABA and substance P in SN without damaging DA containing neurons. Application of GABA-mimetic compounds such as muscimol or diazepam, either systemically or directly into SN, blocked the antipsychotic-induced activation of striatal TH. On the other hand, systemic administration of GABA antagonists such as picrotoxin or isoniazid potentiated the action of haloperidol. The data suggest that GABA terminals in SN, and possibly also substance P terminals in SN, play a role in the mediation of the effect of antipsychotic drugs on the activity of nigrostriatal DA neurons. BIBLIOGRAPHIC REFERENCES: Gale, K., Guidotti, A. and Costa, E.: On the location of dopamine-sensitive adenylate cyclase in substantia nigra. Science 195: 503-505, 1977. Guidotti, A., Gale, K., Toffano, G. and Costa, E.: Regulatory role of GABA neurons on the activation of striatal tyrosine hydroxylase by haloperidol. In Weiner N. and Usden, E. (Eds.): Biochemistry and Function of Monoamines Enzymes. New York, Marcel Dekker, in press, 1977.